Sex differences in body composition but not neuromuscular function following long-term, doxycycline-induced reduction in circulating levels of myostatin in mice

Abstract

Age-related declines in muscle function result from changes in muscle structure and contractile properties, as well as from neural adaptations. Blocking myostatin to drive muscle growth is one potential therapeutic approach. While the effects of myostatin depletion on muscle characteristics are well established, we have very little understanding of its effects on the neural system. Here we assess the effects of long-term, post-developmental myostatin reduction on electrophysiological motor unit characteristics and body composition in aging mice. We used male (N = 21) and female (N = 26) mice containing a tetracycline-inducible system to delete the myostatin gene in skeletal muscle. Starting at 12 months of age, half of the mice were administered doxycycline (tetracycline) through their chow for one year. During that time we measured food intake, body composition, and hindlimb electromyographic responses. Doxycycline-induced myostatin reduction had no effect on motor unit properties for either sex, though significant age-dependent declines in motor unit number occurred in all mice. However, treatment with doxycycline induced different changes in body composition between sexes. All female mice increased in total, lean and fat mass, but doxycycline-treated female mice experienced a significantly larger increase in lean mass than controls. All male mice also increased total and lean mass, but administration of doxycycline had no effect. Additionally, doxycycline-treated male mice maintained their fat mass at baseline levels, while the control group experienced a significant increase from baseline and compared to the doxycycline treated group. Our results show that long-term administration of doxycycline results in body composition adaptations that are distinctive between male and female mice, and that the effects of myostatin reduction are most pronounced during the first three months of treatment. We also report that age-related changes in motor unit number are not offset by reduced myostatin levels, despite increased lean mass exhibited by female mice.

Gendered division of labor in a Celtic community? A comparison of sex differences in entheseal changes and long bone shape and robusticity in thepre‐Romanpopulation of Verona (Italy, third–first centuryBC)

“…In this work we analyzed a single population, and therefore we may assume a broad genetic homogeneity in our sample. However, previous research has shown an effect of sex on the influence of those gene variants on muscle and bone response to mechanical stimuli (Dubrow, Hruby, & Akhter, 2007; Tavoian, Arnold, Mort, & de Lacalle, 2019; van Meurs et al, 2006). The diaphyseal robusticity shown by females in this sample may be the result of their exposure to physically demanding tasks in conjunction with a lower threshold for bone response to biomechanical loading.…”

Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures

“…Targeted deletion of MSTN during skeletal maturity increased masseter mass and bite force in male mice only ( Williams et al, 2015 ). In contrast, long-term MSTN deletion in skeletal muscles increased lean muscle mass only in aged female mice ( Tavoian et al, 2019 ). These discrepancies might be attributable to sex-related differences of MSTN expression itself in skeletal muscles.…”

Sex-Specific Role of Myostatin Signaling in Neonatal Muscle Growth, Denervation Atrophy, and Neuromuscular Contractures

“…52 In contrast, long-term MSTN deletion in skeletal muscles increased lean muscle mass only in aged female mice. 53 These discrepancies might be attributable to sex-related differences of MSTN expression itself in skeletal muscles. Indeed, while men are prone to having higher expression of genes encoding ribosomal and mitochondrial proteins, women tend to have higher gene expression of the ACVR2B receptor.…”